Thjobarbitijiuc acid derivatives



o Ethyl (l-methlj lll bu tllll thio-barbituric Patented Apr. 11, 1939 UNITED STATES PATENT OFFICE- 2.153.129 'rmonmrrumc ACID DERIVATIVES Ernestfivolwiler, Highland Park, and DonaleeL Tabern, Lake Bluii, IlL, assignors to Abbott Laboratories, North tion of Illinois Chicago, 111., a c m- No Drawing. Application April 16, 1934, Serial No. 720,804

5 Claims. (Cl. 260-280) Our invention relates to thio-barbituric acid derivatives, having the structure:

a C0-NH =8 a do-i v-x in which R and R. represent saturated or unsaturated allryl or aryl groups, either the same or different, at least one of which contains more than three carbon atoms, and X represents hydrogen, an alkali or alkaline earth metal, or a primary or secondary alkyl amine; Said compounds are eillcacious as hypnotics and sedatives.

These thio-barbituric acid derivatives are, in

general, as eilective in this regard as or more.

effective than the oxygen analogs, and in addition certain members show a definitely shorter period of hypnotic action. They are rapidly detoxifled in the body, which is of clinical advantage, as, for example, when the compounds are used as surgical anesthetics or pre-anesthetics.

These thio-barbituric acid derivatives may be prepared by several methods, for example, by

the condensation of a malonic ester with thio A satisfactory method oi preparation consists in the condensation of one molecular equivalent of a monoor (ii-substituted malonic ester with one or two molecular equivalents of thio-urea in the presence of two to four molecular equivalents of sodium ethylate. Thesolvent used for this reaction may be alcohol or a hydrocarbon solvent;

a quantityoi the solvent is preferably removed to enable a temperature 01 from to C. to be reached. The impure sodium salt thus formed is dissolved in cold water and precipitated by an acid. Purification may be accomplished by dissowing the barbituric acid derivative in alkali and reprecipitating by acid, followed by recrystallization from alcohol, dilute alcohol, benzene, or other suitable solvent; or by sublimation, or other suitable technique.

qExmul acid Zomba. CONH =8 I-CHaCHLCBaCH do-u-x grams of ethyl (l-methyl butyl) malonic ester is added to a concentrated solution of sodium ethylate prepared from 34 grams of sodium in absolute alcohol; with stirring, 60 grams of finely divided thio-urea is added, and

. the mixture refluxed for 10 hours. Most or all of the solvent is evaporated and the residual mass is dissolved in cold water. The barbituric acid derivative so formed is precipitated by the addition of dilute hydrochloric acid. It may be purified by solution in dilute ammonium hydroxide solution and precipitated by carbon dioxide, iollowed by recrystallization from 95% alcohol. The ethyl.(l-methyl butyl) thio-barbiturlc acid so obtained is a white crystalline solid, melting at 158-159 C. and readily forming salts with alkalies.

' Exam 2 tion oi the salt by carbon dioxide, and recrystallized. The crystals melt at -182" C.

EXAMPLE 3 Ethyl secondaril-butyl thio-barbiturio acid OHrCHa\C 0-K: cnrcnrcn co-x q-x 100 grams of ethyl secondary-butyl malonic ester is added to a solution of 24 grams of sodium in absolute alcohol followed by 44 grams oi thiourea. Alter refluxing for 24 hours, the solvent is removed, the resultant mass heated to 120, and after cooling, the material is dissolved in water.

By precipitating with acetic acid, the crystalline barbituric acid is obtained. It is dissolved in dilute alkali and repreclpitated by carbon dioxide. It melts at 103-165'0. l

of this ester and 22 grams of thio-urea is added to a solution of 14 grams 01' sodium in absolute alcohol. The product is isolated and purified asin Example 3. The crystals melt at 128-130".

Exmu: 6

Benzul allul thio-barbituric acid clmcr co rrs By condensing benml allyl malonic ester with thio-urea and sodium ethylate, as in previous examples, benzyl allyl thio-barbituric acid is obtained, melting at 149-150 C.

. Exams: 7

Ethyl (z-ethul-butul) thio-barbituric acid CHa-OH: co-NH =8 cm-omcn-onflao-ris-x Hr CH;

110 grams of ethyl (2-ethyl-butyl) malonic ester is condensed with 4'4 grams of thlo-urea in a solution of 28 grams of sodium in alcohol. The resultant thio-barbituric acid melts at 138-? C.

Salts The thio-barbituric acids are acid in charac ter, forming salts with alkali and alkaline earth metals and with organic bases. These salts are stable in the solid state and reasonably so in solution.

The sodium salts may be prepared by dissolving one molecular equivalent of the thio-barbituric acid in warm absolute alcohol, which is added to a solution of one atomic equivalent of sodium ethylate in absolute alcohol. Upon evaporation of the alcohol, the sodium salt separates as a crystalline, slightly hygroscopic solid, readily soluble in water. The hydrogen ion concentrations of aqueous solutions of the salts are similar to those of the corresponding omen analogs.

The calcium salts may be produced by dissolving or suspending the thio-barbituric acid in water, alcohol, or dilute alcohol, adding an excess of lime, stirring, filtering, and concentrating the resultant solution. The calcium salts are readily soluble in water. A preferable method in the case of certain of the higher homologs where the calcium salts are less soluble. is the addition of a strong solution of calcium chloride or acetate to a solution of an alkaline earth orammonium salt. The precipitated calcium saltmay be readily illtered oi! and air-dried. Examples: The calcium salts of ethyl (2-ethyl-butyl) thio-barbituric acid and ethyl -methyl-butyl) thio-barbituric acids.

The mono alkyl and di-alkylamine salts may be prepared by dissolving the thio-barbituric acid in a slight excess of the amine, and removing the excess amine. These salts are readily. soluble in water, but are easily hydrolyzed. The lower alkylamine salts in the solid state readily lose the amine, leaving behind the thio-barbituric acid.

The following thio-barbituric acids have been prepared:

M. P. Eth l I-meth l-bu l) thio-barblturic aeid- 158-9 Ethyl iZ-methl-alfyl) thio-barbiturie aci -451 Allyl i -methy -ally thio-barbituric acid"--- 180-2 eth (Z-methyl-allyl) thio-barbiturie acid--- 128-31 Ethyf secondary-bu l-thio-barbituric acid-..-- 163-5 Allyl seeonda -buty thio-barbituric acid"--- 1424' Math 1 (l-me il-butyl) thio-barbiturie acid-.. Wax-like Eth (3-chlorm -butenyl) thio-barbituric acid- 128-30 Dia 1 thio-barblturie acid 134 thyrilo rop'il thio-barbitnrie acid 192' nzyl al yl iobarblturic acid--- 140-50 Ethy n-butyl thiobarbituric acid. 144-6 Ethyl isoamyl thio-barbiturie acid- -7 Phenfl ethy flllobarblturie acid -a- 215-17 Ethy allyl thio-barbituric aeid 172-3 Ethyl (Z-ethyl-butyl) thio-barbituric acid-.. 131-188 We claim as our invention: 1. Anesthetic, sedative and compounds having the formula:

CsHs

sleep producing in which R, is a member-of the group consisting of saturated and unsaturated alkyl groups containing more than 3 carbon atoms, and X is selected from the group consisting of hydrogen, alkali and alkaline earth metals and primary and secondary alkyl amines.

Anesthetic, sedative and sleep producing compounds having the following formula:

selected from the group consisting of hydrogen,

alkali and alkaline earth metals and primary and secondary alkyl amines.

. mamas 3 4. Anesthetic, sedative' and sleep producing 5. Anesthetic, sedative and sleep producing compounds having the following formula: compounds having the formula: cm. oomr a CO-NH 5 t 3H g =8 5 a co-r'r-x m co-rm in which R is a member of the group consisting in which R and R1 are members of the group conoi saturated and unsaturated secondary alkyl sistlng of saturated and unsaturated alkyl radigroups containing more than 8 carbon atoms, and cals, R having at least three carbon atoms and 10 x is selected from the group consisting of'hydro- R1 at least (our carbon atoms, and their salts.

gen, alkali and alkaline earth metals and primary ERNEST H. VOLWILER. and secondary alkyl amines. DONALEE L. TABERN. 

